A symptom of many ophthalmologic and neurologic disorders is photophobia: discomfort and pain from flickering and bright lights. More specifically, photophobia is a key symptom in patients with migraine, both during headache and also in the headache-free inter-ictal period. This clinical observation has been confirmed by systematic behavioral studies demonstrating lower discomfort thresholds for visual stimulation in such patients. There is also evidence that some forms of visual discomfort may be related to signals from intrinsically photosensitive retinal ganglion cells (ipRGCs) that contain the photopigment melanopsin. The three aims of this proposal will test the hypothesis that photophobia associated with migraine headache is related to altered responses to stimulation of melanopsin, as well as characterize the photoreceptor mechanisms that mediate the documented elevated neural response to light observed in migraine with aura. All three aims will employ a digital light integrator to produce spectral modulations that selectively and robustly stimulate individual photopigment classes. We will measure the effect of stimulation directed separately at melanopsin and the cone photoreceptors, as well as interactions between melanopsin and cone signals. Aim 1 will examine direct effects of melanopsin stimulation in healthy human subjects, using three distinct but complementary response measures: behavioral reports of visual discomfort and perception of brightness, fMRI and the pupillary light response. We will examine the specific role of melanopsin in behaviorally-assessed visual discomfort and brightness perception, measure sustained brain responses to direct melanopsin stimulation, and use the pupillary light response to assess individual differences in melanopsin responsivity as well as the stability of these differences over time. Aim 2 will also study healthy control subjects and characterize whether and how melanopsin signals interact with signals from cones, to regulate the response to cone-mediated light flicker. We will measure psychophysical thresholds for detection of cone-mediated flicker and assess how these are affected by changes in the melanopic component of an adapting background light, use fMRI to measure neural correlates of the psychophysical effects, and employ a novel paradigm that allows us to use the sluggish pupillary light response to test the hypothesis that melanopsin signals regulate the response to cone-mediated flicker at an early site along the visual pathways. Aim 3 will build on the results of Aims 1 and 2 to characterize the photoreceptor mechanism of the enhanced neural response to light observed in migraine with aura. We will also measure whether the migraineurs demonstrate systematic differences with controls in either the direct or interactive effects of melanopsin, and whether such differences are related to the enhanced light sensitivity of this patient population.